83 articles - From Friday Oct 07 2022 to Friday Oct 14 2022
Guidelines, position statements, white papers, technical reviews, consensus statements, etc…
meta-analyses and systematic reviews
RCT, clinical trials, retrospective studies, etc…
| Am J Hematol |
Hodgkin lymphoma: 2023 update on diagnosis, risk-stratification, and management. Management of relapsed/refractory disease High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplant, or participation in a clinical trial should be considered. |
Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell-disease-like and common myeloid progenitor-disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor-disease-like and monocyte-disease-like signatures, G7 and G8 had common lymphoid progenitor-disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL. |
Patient characteristics that predict Richter's Transformation in patients with CLL treated with ibrutinib. Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis. |
Risk Factors For Severe Infection And Mortality In Patients With COVID-19 in Patients with Multiple Myeloma And AL Amyloidosis. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p=0.02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p=0.014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p=0.029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p=0.038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p=0.008]. |
The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study. After 7 |
| Ann Oncol |
Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high risk, early breast cancer. No new safety signals were identified including no new cases of acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS). With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. |
Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX) - a randomized phase II trial of the AIO pancreatic cancer group. The primary endpoint, DFS rate of 55% at 18 months (mITT-population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. Median OS (ITT-population), a secondary endpoint, numerically favored the neoadjuvant arm A (25.5mo [95%CI 19.7-29.7]; arm B 16.7mo. [95%CI 11.6-22.2]). There was a difference in chemotherapy exposure with 90% of patients in arm A completing preoperative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for pts. with resectable PDAC. However, the optimal treatment regimen has yet to be defined. |
Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study. Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology. |
Short-term outcomes of chemoradiotherapy and local excision vs total mesorectal excision in T2-T3ab,N0,M0 rectal cancer. A multicentre randomised, controlled, phase III trial (the TAUTEM study). Patients included, tolerance of CRT and its adverse effects, surgical complications (Clavien-Dindo and Comprehensive Complication Index classifications) and pathological results (complete response in the CRT-TEM group) were recorded in both groups. Patients attended follow-up controls for local and systemic relapse. |
Streamlining clinical research: An ESMO awareness call to improve Sponsoring and Monitoring of Clinical Trials. This initiative aspires to streamline clinical research procedures and to become a platform for discussion among al clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients. |
| Blood |
Acquired mutations in BAX confer resistance to BH3-mimetic therapy in Acute Myeloid Leukemia. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represents a novel mechanism of resistance to BH3-mimetics and a potential barrier to longer-term efficacy of drugs targeting BCL-2 in AML. |
GENETIC SUBGROUPS INFORM ON PATHOBIOLOGY IN ADULT AND PEDIATRIC BURKITT LYMPHOMA. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological, diagnostic, and therapeutic strategies. |
Genome edited allogeneic donor 'universal' chimeric antigen receptor T Cells. Improvements in targeting and efficiency has unlocked applications against a wider range of blood malignancies with multiplexed editing incorporated to target HLA molecules, shared antigens and checkpoint pathways. Clinical trials will help establish safety profiles and determine the durability of responses, as well as the role of consolidation by allogeneic transplantation. |
Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking and homeostasis are critically important for the differentiation of neutrophil granulocytes. |
mTOR inhibition attenuates cTfh cell dysregulation and chronic T cell activation in multi-lineage immune cytopenias. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B cell maturation. |
Multiple COVID-19 vaccine doses in CLL and MBL improve immune responses with progressive and high seroconversion. Strong neutralization and T-cell responses had high concordance with high anti-spike levels. Multiple sequential COVID-19 vaccination significantly increased seroconversion and anti-spike antibody levels in CLL and MBL. |
Murine Allogeneic CAR-T Cells Integrated Before or Early After Posttransplant Cyclophosphamide Exert Anti-Tumor Effects. In comparison with infusion on day +5, CAR-T-cell infusion on day 0 demonstrated superior clinical efficacy associated with earlier CAR-T-cell expansion, higher phenotypic CAR-T-cell activation, less CD4+CD25+Foxp3+ CAR-T-cell recovery, and transcriptional changes suggesting increased activation of CD4+ CAR-T-cells and more cytotoxic CD8+ CAR-T-cells. This study provides mechanistic insight into PTCy's impact on graft-versus-tumor immunity and describes novel approaches to integrate CAR-T-cells and allo-HCT that may compensate for deficiencies of each individual approach. |
PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML. |
RUNX1-deficient human megakaryocytes demonstrate thrombopoietic, and platelet half-life and functional defects. A small-molecule inhibitor RepSox, which blocks the transforming-growth factor beta pathway, and which rescued defective megakaryopoiesis in vitro, corrected the thrombopoietic defect, platelet half-life and agonist response, and thrombus formation in NSG/ VWFR1326H mice. Thus, this model recapitulates the defect in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates, for the first time, reversal of RUNX1 deficiency's hemostatic defects by a drug. |
Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be evaluated further in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies. |
| Blood Adv |
A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE / PBMTC 1202 study. The cGVHD diagnostic classifier achieved an AUC of 0.89 with a positive predictive value of 82% and negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. |
A single administration of hIL-7-hyFc induces long-lasting T-cell expansion with maintained functions and TCR diversity. Our results suggest that hIL-7-hyFc administration induced a sustained increase in the numbers of CD8+ and CD4+ T cells, but not regulatory T cells, without qualitative changes. These results support the potential of hIL-7-hyFc as a treatment for patients with compromised T-cell immunity or as a vaccine adjuvant. |
Clonal hematopoiesis in patients with stem cell mobilization failure: a nested case-control study. We conclude that CH at low VAF (1-10%) is common at time of stem cell mobilization. TP53 mutations and PPM1D mutations associate with poor mobilization potential and their role in subsequent development of t-MN in these individuals should be established. |
Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity. g., aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared to COX inhibitors. |
GATA1 controls numbers of hematopoietic progenitors and their response to autoimmune neuroinflammation. Examination of HSPCs revealed fewer HSCs and myeloid cell progenitors in |
MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype. |
RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS. Strikingly, while RUNX1 deficiency was responsible for altered transcription in both single and double mutants, it also induced dramatic changes in global splicing, as seen with mutant SRSF2, and only their combination induced mis-splicing of genes selectively enriched in the DNA damage response and cell cycle checkpoint pathways. Collectively, these data reveal the convergent impact of a prototypic MDS-associated double mutant on RNA processing and suggest that aberrant DNA damage repair and cell cycle regulation critically contribute to MDS development. |
| Haematologica |
A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. |
Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through inhibition of autophagy. CG-806 further significantly reduced AML burden and extended survival in an in vivo PDX leukemia murine model of FLT3 inhibitorresistant FLT3-ITD/TKD double mutant primary AML. Taken together, CG-806 exerts a unique mechanistic action and pre-clinical activity, suggesting further development in FLT3 wild-type and mutant AML. |
Defective binding of ETS1 and STAT4 due to a mutation in the promoter region of THPO as a novel mechanism of congenital amegakaryocytic thrombocytopenia. Based on these findings, the patient was treated with the THPOmimetic agent eltrombopag, inducing a significant increase in platelet count and stable remission of bleeding symptoms. Herein, we report a novel pathogenic variant responsible for CAMT and provide new insights into the mechanisms regulating the transcription of the THPO gene. |
Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients. |
Variation and impact of polygenic hematological traits in monogenic sickle cell disease. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 39% (P = 0.0006). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives. |
| J Hematol Oncol |
Combination of oral STING agonist MSA-2 and anti-TGF-ß/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors. Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models. |
CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality. Membrane-anchored IL30 expressed by human PC cells shares a tumor progression programs with its murine homolog and, via juxtacrine signals, steers a complex network of PC driver and immunity genes promoting prostate oncogenesis. The efficacy of CRISPR/Cas9-mediated targeting of IL30 in curbing PC progression paves the way for its clinical use. |
CXCL13 chemokine is a novel player in multiple myeloma osteolytic microenvironment, M2 macrophage polarization, and tumor progression. Altogether, our findings suggest that bidirectional interactions of MF with MM tumor cells result in M2 MF polarization, CXCL13 induction, and subsequent OC activation, enhancing their ability to support bone resorption and MM progression. CXCL13 may thus serve as a potential novel target in MM. |
| Lancet Haematol |
Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma. Funding Janssen Research & Development and Legend Biotech USA. |
Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted. Funding Bristol Myers Squibb. |
UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. Servier. |
| Leukemia |
Autophagy inhibition impairs leukemia stem cell function in FLT3-ITD AML but has antagonistic interactions with tyrosine kinase inhibition. We further show that TKI-mediated targeting of AML LSC and committed progenitors was p53-dependent, and that autophagy inhibition enhanced p53 activity and increased TKI-mediated targeting of AML progenitors, but decreased p53 activity in LSC and reduced TKI-mediated LSC inhibition. These results provide new insights into the role of autophagy in differentially regulating AML stem and progenitor cells, reveal unexpected antagonistic effects of combined oncogenic tyrosine kinase inhibition and autophagy inhibition in AML LSC, and suggest an alternative approach to target AML LSC quiescence and regenerative potential. |
Comparison of the revised 4th (2016) and 5th (2022) editions of the World Health Organization classification of myelodysplastic neoplasms. Subjects re-classified as MDS-biTP53 and MDS-f had significantly briefer median survivals compared with other MDS sub-types (10 months, [8, 12 months] and 15 months [8, 23 months]). In conclusion, our analyses support the refinements made in the WHO 2022 proposal. |
DDX41 coordinates RNA splicing and transcriptional elongation to prevent DNA replication stress in hematopoietic cells. Although the degree of DNA replication stress acquired in S phase is small, cells undergo mitosis with under-replicated DNA being remained, resulting in micronuclei formation and significant DNA damage, thus leading to impaired cell proliferation and genomic instability. These processes may be responsible for disease phenotypes associated with DDX41 mutations. |
Disturbances in microbial skin recolonization and cutaneous immune response following allogeneic stem cell transfer. Further, co-localization of CD45 + leukocytes and staphylococci was observed in the skin of aGVHD patients even before disease development and paralleled with upregulated genes required for antigen-presentation in mononuclear phagocytes. Overall, our data reveal disturbances of the skin microbiome as well as cutaneous immune response in HSCT recipients with changes associated with cutaneous aGVHD. |
JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL. This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients. |
| Thromb Haemost |
Hyperresponsive Platelets and a Reduced Platelet Granule Release Capacity Are Associated with Severity and Mortality in COVID-19 Patients. Using an accessible agonist-induced platelet granule ATP release assay, we show that platelet hyper-responsiveness and reduced platelet GRC in COVID-19 patients were associated with critical illness and mortality. |
Knowledge gaps for prophylactic antithrombotic agents use in patients with COVID-19: Insights on new variants, vaccination and emerging antivirals. In conclusion, although the mortality benefit of mass vaccination and the early promising results of the new antiviral therapies are well-known, we were unable to find clinical evidence on whether vaccination, the use of novel antiviral agents, and emerging viral variants have affected the incidence rate of thrombotic events or impacted the efficacy of prophylactic antithrombotic therapy in patients with COVID-19. Analyses from existing trials and large-scale registries can provide interim knowledge and any findings of relevance should be incorporated in the design of future trials. |
Selective serotonin reuptake inhibitor use and risk of major bleeding during treatment with vitamin K antagonists: results of a cohort study. SSRI use is associated with an increased risk of high INR and might be associated with major bleeding. The risk of a high INR was slightly more elevated for CYP2C9 inhibiting SSRI users, suggesting there might be a pharmacokinetic interaction (by CYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation. |
Plenty of the editorials are available as full text through the publisher website using the provided link
| Am J Hematol |
| Blood Cancer J |
Does the pursuit of scientific excellence serve or hamper translational medical research: an historical perspective from hematological malignancies. We then discuss the history of arsenic trioxide as additional APL therapy, and the repurposing of thalidomide as effective multiple myeloma therapy. These stories have surprising elements of commonality that demand debate about the modern-day hard and soft governance of medical research and whether these processes appropriately align the priorities of advancing scientific knowledge and the need of patients. |
| J Hematol Oncol |
Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. Additionally, RTK-targeted therapies and immune checkpoint-based immunotherapies are also discussed. Our analysis of existing challenges and potential opportunities in drug development may advance solid tumor treatment in the future. |
The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy. However, excessive or uncontrolled cell death might lead to tissue damage, acute inflammation, or even cytokine release syndrome, which facilitates tumor progression or recurrence. Herein, we aimed to describe the molecular mechanisms of pyroptosis, to highlight and discuss the challenges and opportunities for activating pyroptosis pathways through various oncologic therapies in multiple pediatric neoplasms, including osteosarcoma, neuroblastoma, leukemia, lymphoma, and brain tumors. |
| Lancet Haematol |
Current status of phase 3 clinical trials in high-risk myelodysplastic syndromes: pitfalls and recommendations. Despite initial encouraging results, two registration trials from 2021 and 2022 have not been successful in improving outcomes when compared with single-agent hypomethylating agents. Here, I summarise the current status of ongoing phase 3 trials for patients with untreated high-risk myelodysplastic syndromes and provide some suggestions for future designs. |
misc publications eg case reports, tools of the trade, images of the month, etc…
| Am J Hematol |
| Blood |
| Blood Adv |
| Lancet Haematol |
| Leukemia |
Letters to the editors and authors’ replies
| Ann Oncol |
| Blood Adv |
| Blood Cancer J |